Pancreatic diseases represent a major, poorly treated health-care problem in the United States. Unfortunately, once established the devastating effects of severe acute pancreatitis or chronic pancreatitis cannot be reversed. We believe true advances in the treatment of pancreatic disease, as in other diseases, rest in the early identification of at-risk individuals and in the prevention or limitation of the disease. Thus, the goal of our program is to determine the genetic and molecular mechanisms that predispose individuals to recurrent acute pancreatitis and chronic pancreatitis and to identify therapeutic targets. Our Aims are to identify new mutations in susceptibility genes (starting with our chromosome 12 locus), and define the modifier genes and environmental factors that alter phenotypic expression and progression of pancreatic disease through fibrosis, calcifications, diabetes and disabling pain patterns. This will be accomplished by complementary laboratory techniques and statistical analysis and facilitated by expanding and revisiting our valuable family genetic resources. This proposal complements the North American Pancreas Study 2 (NAPS2) grant, a genetic epidemiology study that determines the prevalence of major pancreatitis associated gene mutations in the United States. The NAPS2 focuses on NON-familial pancreatitis, whereas the current hereditary pancreatitis (HP) Study focuses on families. The interaction between these grants occurs through referral of families that are identified in the NAPS2 study to the HP Study, and the determining whether genes found in families in the HP Study are generally important in US populations. The HP and familial pancreatitis studies are especially important because of the statistical power of family studies and the ability to detect modifier genes in a uniform background of susceptibility factors.